title: Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network.
abstract: Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here, we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over-expression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3'-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders. Celastrol, a plant-derived triterpene, has shown neuroprotective effects. However, little is known regarding the effect of celastrol on cadmium (Cd) neurotoxicity. This study underscores that celastrol prevents Cd-induced neuronal apoptosis via inhibiting activation of JNK (c-Jun N-terminal kinase) and Akt/mTOR network. Celastrol suppresses Cd-activated Akt/mTOR pathway by elevating PTEN (phosphatase and tensin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Chenjian
authors.initials: C
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Yijiao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Los Angeles, USA.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019256:Cadmium Chloride / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D004785:Environmental Pollutants; D018696:Neuroprotective Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D019256:Cadmium Chloride; C050414:celastrol
keywords: Celastrol; apoptosis; c-Jun N-terminal kinase; cadmium; mammalian target of rapamycin; phosphatase and tensin homolog on chromosome 10